Culture

Washington, DC - March 20, 2020 - SARS-CoV-2, the virus that causes COVID-19 disease is more transmissible, but has a lower mortality rate than its sibling, SARS-CoV, according to a review article published this week in Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology.

In humans, coronaviruses cause mainly respiratory infections. Individuals with SARS-CoV-2 may remain asymptomatic for 2 to 14 days post-infection and some individuals likely transmit the virus without developing disease symptoms.

So far, the most promising compound for treating COVID-19 is the antiviral, remdesivir. It is currently in clinical trials for treating Ebola virus infections.

Remdesivir was recently tested in a non-human primate model of MERS-CoV infection. Prophylactic treatment 24 hours prior to inoculation prevented MERS-CoV from causing clinical disease and inhibited viral replication in lung tissues, preventing formation of lung lesions. Initiation of treatment 12 hours after virus inoculation was similarly effective.

Remdesivir has also shown effectiveness against a wide range of coronaviruses. It has already undergone safety testing in clinical trials for Ebola, thereby reducing the time that would be necessary for conducting clinical trials for SARS-CoV-2.

Nonetheless, much work needs to be done to gain a better understanding of the mechanics of SARS-CoV-2. For example, understanding how SARS-CoV-2 interacts with the host ACE2 receptor--by which SARS-CoV-2 gains entry into the host (whether human or animal)--might reveal how this virus overcame the species barrier between animals and humans. This could also lead to design of new antivirals.

Although coronaviruses are common in bats, no direct animal source of the epidemic has been identified to date, according to the report. "It is critical to identify the intermediate species to stop the current spread and to prevent future human SARS-related coronavirus epidemics," the researchers write.

Research published in the journal Microbiology has found that a unique type of algae, usually only seen on the shells of turtles, affects the surrounding microbial communities.

It is hoped that these findings can be applied to support the conservation of turtles. Previous research has shown that a diverse microbiome can protect animals against infections.

The research aimed to understand how the microbiome - a complex community of micro-organisms - varies around the body of Krefft's river turtles. Samples were assessed from inside the mouth, the top of the head and parts of the shells of six turtles collected from Ross River in Queensland, Australia.

The research team, based at the University of New England and James Cook University, then used a technique called high-throughput sequencingto identify which micro-organisms were present on the turtles, using DNA sequencing to determine which bacteria are present, and their abundance.

Previous research has shown that animals in captivity often have less diverse microbiomes, which could affect their long-term health. Dr Donald McKnight, who led the research, said: "Successful conservation efforts inherently require a thorough understanding of an organism's ecology, and we are increasingly realising that microbiomes are a really important part of host ecology. So, filling that gap in our knowledge is important, particularly for animals like turtles.

"Turtles are one of the most imperilled groups of animals. Nearly two-thirds of all turtle species are either threatened or endangered, and efforts to conserve them often involve breeding turtles in captivity or collecting eggs from wild turtles and raising them in captivity until they are large enough to be released. Studies on other animals have, however, shown that captivity can alter the microbiome."

The results showed that the microbiome of the turtles' shells varied, depending on whether algae was present. "It is really interesting that even something like the presence of algae can affect the microbiome" said Dr McKnight. "The algae on turtle's shells is fascinating. It's actually a unique genus that grows almost exclusively on turtles."

The algae seen on turtles' shells has many important roles, including providing camouflage and acting as a home for small crustaceans and dispersing seeds. "Our study adds to those roles by showing that algae also affects the microbiome. The mechanism through which it affects the microbiome isn't clear yet, but there are several possibilities. For example, it might compete with some bacteria in order to access the turtles' shells. It may also provide a habitat for bacteria that don't grow well on just the shell itself. Another possibility is that it could retain moisture while turtles bask, and that could affect which species of bacteria grow well. Our study is just an early step in understanding turtle microbiomes, but hopefully future work will build on it and test some of these possibilities." said Dr McKnight.

It is important to understand what the microbiome looks like on all parts of the turtle, according to Dr McKnight. He said, "Studies on other animals, including humans, have often found that different parts of the body have different microbiomes. So, it makes sense that this would be true for turtles as well, but it is still really important to test these things rather making assumptions

"We don't really know how this affects the success of efforts to conserve turtles by raising them in captivity and releasing them, but it could be an important part of the puzzle. Our study contributes to this by documenting the microbiomes of wild turtles, so that we have a baseline to compare to. More studies are needed to look at whether captivity affects microbiomes in turtles and how those shifts affect conservation."

Dr McKnight hopes to continue to research turtle microbiomes: "We are in the early stages of looking at how various environmental and demographic factors affect turtle microbiomes. For example, we want to see if they shift seasonally, if diet affects them, and if different ages and sexes have different microbiomes."

As scientists scramble to learn more about the SARS-CoV-2 coronavirus, two recent studies of the virus' genome reached controversial conclusions: namely, that snakes are intermediate hosts of the new virus, and that a key coronavirus protein shares "uncanny similarities" with an HIV-1 protein. Now, a study in ACS' Journal of Proteome Research refutes both ideas and suggests that scaly, anteater-like animals called pangolins are the missing link for SARS-CoV-2 transmission between bats and humans.

Understanding where SARS-CoV-2 -- the virus that caused the COVID-19 pandemic ¬-- came from and how it spreads is important for its control and treatment. Most experts agree that bats are a natural reservoir of SARS-CoV-2, but an intermediate host was needed for it to jump from bats to humans. A recent study that analyzed the new virus' genome suggested snakes as this host, despite the fact that coronaviruses are only known to infect mammals and birds. Meanwhile, an unrelated study compared the sequence of the spike protein -- a key protein responsible for getting the virus into mammalian cells -- of the new coronavirus to that of HIV-1, noting unexpected similarities. Although the authors withdrew this preprint manuscript after scientific criticism, it spawned rumors and conspiracy theories that the new coronavirus could have been engineered in a lab. Yang Zhang and colleagues wanted to conduct a more careful and complete analysis of SARS-CoV-2 DNA and protein sequences to resolve these issues.

Compared to the previous studies, the researchers used larger data sets and newer, more accurate bioinformatics methods and databases to analyze the SARS-CoV-2 genome. They found that, in contrast to the claim that four regions of the spike protein were uniquely shared between SARS-CoV-2 and HIV-1, the four sequence segments could be found in other viruses, including bat coronavirus. After uncovering an error in the analysis that suggested snakes as an intermediate host, the team searched DNA and protein sequences isolated from pangolin tissues for ones similar to SARS-CoV-2. The researchers identified protein sequences in sick animals' lungs that were 91% identical to the human virus' proteins. Moreover, the receptor binding domain of the spike protein from the pangolin coronavirus had only five amino acid differences from SARS-CoV-2, compared with 19 differences between the human and bat viral proteins. This evidence points to the pangolin as the most likely intermediate host for the new coronavirus, but additional intermediate hosts could be possible, the researchers say.

Maintaining vitamin D receptor (VDR) levels in pancreatic cells that synthesize and secrete insulin (β cells) could contribute to protecting against the development of diabetes and counteract pancreatic cell damage caused by the progression of the disease. This is suggested by a study conducted by researchers of the CIBER's area of Diabetes and Associated Metabolic Diseases (CIBERDEM) at the Universitat Autònoma de Barcelona (UAB), which points to this receptor as a potential therapeutic target in the prevention and treatment of the disease.

Vitamin D deficiency has been associated with a greater prevalence of both type 1 (T1D) and type 2 (T2D) diabetes, and the relation of this disease with variations in the vitamin D receptor gene has also been described. Nevertheless, the specific participation of this vitamin receptor in the development of the disease, specifically in the β cells, continues to be unknown. That is why this new study has focused its efforts on understanding the role played by the VDR of these pancreatic cells in the development of diabetes, by analyzing its behavior in mice.

Decreased VDR Expression in Diabetics

Researchers observed lower VDR expression in the pancreatic islets of mice with both type 1 and type 2 diabetes. In addition, they also demonstrated that the overexpression of VDR in β cells of diabetic mice counteracted the disease, while at the same time proving that sustained levels of vitamin D receptors in these cells could preserve their mass and function and protect against diabetes.

These results suggest that maintaining VDR expression could be essential in counteracting damage to β cells and protect against the development of the disease. "Sustained VDR levels protected transgenic mice from developing severe hyperglycemia, partially preserving the mass of β cells, thereby reducing local inflammation and diabetes", explains Alba Casellas, CIBERDEM researcher at the Centre for Animal Biotechnology and Gene Therapy (CBATEG) at the Universitat Autònoma de Barcelona and coordinator of the study. She goes on to say that, "all of this reveals an unprecedented role of the vitamin D receptor in the pathophysiology of diabetes".

Glucose Stimulates the Vitamin D Receptor

The researchers also confirmed that VDR expression was negatively correlated with circulating sugar levels, i.e., glucose stimulates VDR: "Unexpectedly, we demonstrated that the vitamin D receptor decreases when circulating glucose levels are physiologically low, such as after fasting". In relating this to the characteristics of pancreatic cells in diabetic individuals, what stood out was that "these results could be explained due to the fact that diabetes is associated with low intracellular glucose levels".

Usefulness of Vitamin D in Treating Diabetes

Although the benefits of supplementing with vitamin D as a way to prevent diabetes have been widely reported, clinical data on its effectiveness in improving the state of diabetes are controversial. "Discrepancies in the effectiveness of vitamin D supplements can be due to the negative regulation of the VDR during diabetes", Dr Casellas points out in view of these results.

Therefore, the authors suggest that to achieve positive results, the dosage regimen of vitamin D supplementation must be scheduled in the absence of VDR expression decrease. "Therefore, future strategies for the treatment of diabetes should be based on better knowledge of the mechanisms subjacent to the negative regulation of VDR during diabetes and focus on restoring VDR levels", they conclude.

Most ovarian cancer starts in fallopian tubes. Then it sloughs from its site of origin and floats around in fluid until finding new sites of attachment. It's not easy for cancer cells to survive away from their moorings. Observations by ovarian cancer doctors at University of Colorado Cancer Center and elsewhere hint at how they might do it: These doctors have seen that ovarian cancer cells often collect in tissues with high fat content. Could these cells be somehow using fat to survive the journey from their point of origin to their sites of growth?

Benjamin Bitler, PhD, and CU Cancer Center colleagues asked this question at a molecular level. The work now results in a study published in the journal Molecular Cancer Research showing that when these ovarian cancer cells become detached from their point of origin, they shift to using fats as an energy source. Bitler and colleagues also show how these cells make the shift: The enzyme CPT1A may control how much fat these cancer cells can burn, suggesting that limiting these cells' access to CPT1A may starve them of the resources they need to spread.

"When they break off, they metabolically shift to use fats more - it allows these cells to survive and then they seek out or are able to colonize fatty tissue. It looked like CPT1A was the rate-limiting step in their ability to do this," says Bitler, who is also an assistant professor in the CU School of Medicine Department of Obstetrics & Gynecology.

Interestingly, Bitler was in a serendipitous position to delve deeper into the role of CPT1A in ovarian cancer dissemination. That's because one of the world's experts on this enzyme happens to work on the same campus. The laboratory of Isabel Schlaepfer, PhD, had been working with funding from the American Cancer Society to explore the role of CPT1A in the progression of prostate cancer.

"With Isabel's lab, we were able to demonstrate that, yes, the cells become more dependent on fatty acids to survive the attachment-free environment. For example, we showed that by adding fatty acids to a model of ovarian cancer cells in suspension, we could prevent these cells from dying," Bitler says.

Likewise (and oppositely), the group was also able to show that by knocking down CPT1A, they could keep ovarian cancer cells from spreading in cell-culture studies and slow the spread of human cancer cells grown in mouse models.

"It didn't completely abolish ovarian cancer cells' capacity to go to fat-rich sites, but it reduced it pretty dramatically," he says.

Not only was Bitler able to work with Schlaepfer on better understanding the role of CPT1A on the spread of ovarian cancer cells, but he is now working with another on-campus collaborator, Brad Corr, MD, to bring this strategy to patients who need it.

"There's a drug called etomoxir that inhibits CPT1A and has been tested as a preventative for congestive heart failure," Bitler says. Clinical trials of preventive medicines have a very low tolerance for side-effects, and in the case of etomoxir with congestive heart failure, the risks outweighed the benefits. But in the context of treating cancer, Bitler suggests that the drug's risk would be well within (and even much less than) risks of existing medicines.

"We are working with Brad [Corr] to move forward with this. The question is where exactly to put etomoxir with respect to patient treatment," Bitler says. He explains that a major issue in the treatment of ovarian cancer is the disease's ability to resist chemotherapy. "The cells we've been studying resist cell death because they need to disseminate. Avoiding cell death is at the heart of chemoresistance as well," he says.

The funding from the American Cancer Society to first author, Brandon Sawyer, MD, played an important role in the development of this study and has resulted in additional grants submitted to the National Institutes of Health with the goal of bringing this promising strategy from the laboratory to the clinic.

"Our hope is that we could use etomoxir to treat chemo-resistant disease," Bitler says.

ITHACA, N.Y. - Cornell University astronomers have created five models representing key points from our planet's evolution, like chemical snapshots through Earth's own geologic epochs.

The models will be spectral templates for astronomers to use in the approaching new era of powerful telescopes, and in the hunt for Earth-like planets in distant solar systems.

"These new generation of space- and ground-based telescopes coupled with our models will allow us to identify planets like our Earth out to about 50 to 100 light-years away," said Lisa Kaltenegger, associate professor of astronomy and director of the Carl Sagan Institute.

For the research and model development, Kaltenegger, doctoral student Jack Madden and Zifan Lin authored "High-Resolution Transmission Spectra of Earth through Geological Time," published in Astrophysical Journal Letters.

"Using our own Earth as the key, we modeled five distinct Earth epochs to provide a template for how we can characterize a potential exo-Earth - from a young, prebiotic Earth to our modern world," she said. "The models also allow us to explore at what point in Earth's evolution a distant observer could identify life on the universe's 'pale blue dots' and other worlds like them."

Kaltenegger and her team created atmospheric models that match the Earth of 3.9 billion years ago, a prebiotic Earth, when carbon dioxide densely cloaked the young planet. A second throwback model chemically depicts a planet free of oxygen, an anoxic Earth, going back 3.5 billion years. Three other models reveal the rise of oxygen in the atmosphere from a 0.2% concentration to modern-day levels of 21%.

"Our Earth and the air we breathe have changed drastically since Earth formed 4.5 billions years ago," Kaltenegger said, "and for the first time, this paper addresses how astronomers trying to find worlds like ours, could spot young to modern Earth-like planets in transit, using our own Earth's history as a template."

In Earth's history, the timeline of the rise of oxygen and its abundancy is not clear, Kaltenegger said. But, if astronomers can find exoplanets with nearly 1% of Earth's current oxygen levels, those scientists will begin to find emerging biology, ozone and methane - and can match it to ages of the Earth templates.

"Our transmission spectra show atmospheric features, which would show a remote observer that Earth had a biosphere as early as about 2 billion years ago," Kaltenegger said.

Using forthcoming telescopes like NASA's James Webb Space Telescope, scheduled to launch in March 2021, or the Extremely Large Telescope in Antofagasta, Chile, scheduled for first light in 2025, astronomers could watch as an exoplanet transits in front of its host star, revealing the planet's atmosphere.

"Once the exoplanet transits and blocks out part of its host star, we can decipher its atmospheric spectral signatures," Kaltenegger said. "Using Earth's geologic history as a key, we can more easily spot the chemical signs of life on the distant exoplanets."

The cerebral cortex is the relatively thin, folded, outer "gray matter" layer of the brain crucial for thinking, information processing, memory, and attention. Not much has been revealed about the genetic underpinnings that influence the size of the cortex's surface area and its thickness, both of which have previously been linked to various psychiatric traits, including schizophrenia, bipolar disorder, depression, attention deficit hyperactivity disorder (ADHD), and autism.

Now, for the first time, more 360 scientists from 184 different institutions - including UNC-Chapel Hill - have contributed to a global effort to find more than 200 regions of the genome and more than 300 specific genetic variations that affect the structure of the cerebral cortex and likely play important roles in psychiatric and neurological conditions.

The study, published in Science, was led by co-senior authors Jason Stein, PhD, assistant professor in the Department of Genetics at the UNC School of Medicine; Sarah Medland, PhD, senior research fellow at the QIMR Berghofer Medical Research Institute in Australia; and Paul Thompson, PhD, associate director of the Mark and Mary Stevens Neuroimaging and Informatics Institute at the University of Southern California. Ten years ago, these scientists cofounded the ENIGMA Consortium, an international research network that has brought together hundreds of imaging genomics researchers to understand brain structure, function, and disease based on brain imaging and genetic data.

"This study was only possible due to a huge scientific collaboration of more than 60 sites involved in MRI scanning and genotyping participants," Stein said. "This study is the crown jewel of the ENIGMA Consortium, so far."

The researchers studied MRI scans and DNA from more than 50,000 people to identify 306 genetic variants that influence brain structure in order to shed light on how genetics contribute to differences in the cerebral cortex of individuals. Genetic variants or variations are simply the slight genetic differences that make us unique. Generally speaking, some variants contribute to differences such as hair color or blood type. Some are involved in diseases. Most of the millions of genetic variants, though, have no known significance. This is why pinpointing genetic variants associated with cortex size and structure is a big deal. Stein and colleagues consider their new genetic roadmap of the brain a sort of "Rosetta stone" that will help translate how some genes impact physical brain structure and neurological consequences for individuals.

Among the findings of the research published in Science:

Some genetic variants are associated with cortical folding, measured as surface area, while other genetic variants are associated with the thickness of the cortex.

Genes that determine surface area are related to very early development in the fetal cortex, while thickness appears to be driven by genes active in the adult cortex.

People at genetic risk for depression or insomnia are genetically inclined toward having lower surface area, while people with a genetic risk for Parkinson's disease tend to have higher surface area.

The vast scale of the project allowed the discovery of specific genes that drive brain development and aging in people worldwide.

"Most of our previous understanding of genes affecting the brain are from model systems, like mice," Stein said. "With mice, we can find genes, knock out genes, or over express genes to see how they influence the structure or function of the brain. But there are a couple of problems with this."

One problem is, quite simply, a mouse is not a human. There are many human-specific features that scientists can only study in the human brain.

"The genetic basis for a mouse is very different than the genetic basis for humans," Stein said, "especially in in the noncoding regions of the genome."

Genes contain DNA, the basic human code that, when translated into action, creates proteins that "do" things, such as help your finger muscles type or your heart beat or your liver process toxins. But only about 3 percent of the human genome codes for proteins. The vast majority of the human genome is called the noncoding genome. Much of this region is not shared between mice and humans. This noncoding genome consists of tiny molecular switches that can modulate the expression of other genes. These switches don't directly alter the function of a protein, but they can affect the amounts of a protein that is expressed. Turns out, most genetic variants associated with psychiatric disorders are found in the noncoding region of the genome.

These findings can now be a resource for scientists to help answer important questions about the genetic influences on the brain and how they relate to numerous conditions.

AURORA, Colo. (March 26, 2020) - Assessing adverse childhood experiences and current anxiety and depression symptoms may help ease cognitive distress in women who have undergone a surgical menopause for cancer risk-reduction, or RRSO, according to a new study published in Menopause.

Researchers, including Dr. Neill Epperson of the University of Colorado Anschutz Medical Campus, remotely collected extensive cognitive data from women across the nation. 552 women who are BRCA1 and BRCA2 mutation carriers and have undergone RRSO completed the assessments, which measured executive function (a cognitive process that allows individuals to manage information in a planful versus reactive manner), exposure to early life stress, and mood symptoms.

Results show that adverse childhood experiences (ACE) were associated with more severe symptoms of executive dysfunction and worse performances on cognitive tasks post-surgical menopause. Changes in mood, such as anxiety and depressive symptoms, partially mediated ACE associations on subjective and objective measures of executive function. These findings indicate that assessing history of childhood adversity and current anxiety and depression symptoms may help to identify women who will experience executive cognitive complaints after surgical menopause.

This research emphasizes the importance of considering psychological state during other medical procedures. "We can't change the past for women who have experienced serious childhood adversities such as abuse, neglect, divorce, parental substance abuse, or exposure to domestic violence, but we can identify a patient population that is easily assessed for these ACEs as well as current negative mood symptoms," said Epperson, study lead investigator and professor and Chair of psychiatry at the University of Colorado School of Medicine. "Our hope is that assessment of childhood adversity and history of depression and anxiety would become part of the pre-surgical risk-benefit discussion between patients and their doctors."

"Many women have told me over the years that their doctor did not warn them about the potential brain effects of undergoing a surgical menopause. While these women may have made the same decision regarding surgery given its life preserving benefits, they indicated that they wish they had been informed about the potential cognitive and mood effects so that they could be prepared and seek treatment sooner", says Epperson.

Highly focused, intense doses of radiation called stereotactic ablative radiation (SABR) may slow progression of disease in a subset of men with hormone-sensitive prostate cancers that have spread to a few separate sites in the body, according to results of a phase II clinical trial of the therapy.

The trial, called ORIOLE (Primary outcomes of a Phase II randomized trial of observation versus stereotactic ablative radiation for oligometastatic prostate cancer), and led by Johns Hopkins Kimmel Cancer Center researchers since 2016, compared the effectiveness of SABR versus "wait and watch" observation in recurrent cases of oligometastatic prostate cancer.

"It has been a longstanding question, especially important now in the era of immunotherapy, whether any type of radiation, and SABR specifically, can stimulate the immune system," Tran said. "Our trial offers the best data to date to suggest that SABR can cause a systemic immune response."

Oligometastatic cancers are those that have spread from a primary tumor to one to three sites within the body. Of the estimated 1.3 million men worldwide newly diagnosed with prostate cancer each year, some 20% have metastatic disease, although it's unclear what percentage of those overall have oligometastatic cancers. Prostate cancer is the third most common cancer and the most common cancer among men in the United States, resulting in about 30,000 deaths annually. Metastatic prostate cancer is incurable, and men with recurrent hormone-sensitive cancers may prefer to delay one of the standard treatments, an antihormone therapy called androgen deprivation therapy. It often causes unpleasant side effects, including erectile disfunction, loss of bone density leading to fractures, loss of muscle mass and physical strength, fatigue, weight gain and growth of breast tissue among other things.

A report on the study is published March 26 in the journal JAMA Oncology.

Among the 54 men enrolled in the trial, the disease progressed within six months in seven out of 36 (19%) of participants treated with SABR, compared to 11 out of 18 participants (61%) undergoing observation alone. The risk of new cancers at six months was also lower, occurring in 16% of those receiving SABR compared to 63% of those under observation.

There were no significant differences in clinically meaningful side effects or in reports of pain related to the treatment between the two groups, the study found. The average age of the men on the ORIOLE trial were 68-years old, and most participants were Caucasian.

Analysis of immune system white cells in blood drawn from the patients indicated that SABR treatment was associated with an expanded population of T cells, suggesting that the treatment stimulated a full-body immune system response to their cancers, according to the study leader Phuoc Tran, M.D., Ph.D., professor of radiation oncology and molecular radiation sciences at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Kimmel Cancer Center. Tran co-directs the Kimmel Cancer Center's Cancer Invasion and Metastasis program with Andrew Ewald, Ph.D., and Ashani Weeraratna, Ph.D., aimed at studying the process by which cancers spread, to expand and develop better treatments for patients with advanced cancers.

The findings suggest SABR might be usefully paired with other immunotherapies to treat recurrent oligometastatic prostate cancers, but Tran cautioned that any potential benefits of such combined therapy will need to be tested in future clinical trials.

The research team also detected a set of tumor mutations in genes known to be important for suppressing cancer development in some patients that correlated with a higher risk of cancer progression even among those undergoing SABR. "This may be a molecular signature which is indicative of the underlying biology of the patient's cancer," said Tran.

The biomarker could help clinicians know "which patients are going to benefit the most from a metastasis-directed therapy like SABR" compared to a systemic treatment such as chemotherapy, Tran explained.

The ORIOLE results also suggest that SABR treatment may remove or affect signals that promote the development of micrometastases in recurrent oligometastatic prostate cancer, rather than just "resetting" the clock on the disease until metastases grow large again, said Tran.

Tran and team will continue with phase II studies to determine if they can increase the number of participants with slower disease progression. In the ORIOLE trial, patients with metastatic lesions in the bone were most likely to have their cancers recur in a new bone site. To target these new metastatic bone lesions, Tran and colleagues have another clinical trial called RAVENS that combines SABR with a drug called radium-223 (Xofigo®) that targets metastatic cancer in the bones.

MADISON, Wis. -- Removing a gene from the cells that produce insulin prevents mice from developing Type 1 diabetes by sparing the cells an attack from their own immune system, a new UW-Madison study shows.

The cellular sleight-of-hand may suggest ways to prevent Type 1 diabetes in high-risk individuals, as well as other diseases in which the immune system targets the body's own cells.

People with Type 1 diabetes -- once called juvenile diabetes -- make little or no insulin, a hormone necessary to make energy from the sugar in their blood. At an early stage in the disease, their immune system's frontline soldiers, called T cells, incorrectly identify insulin-producing beta cells as a threat and kill them, leading to complete insulin deficiency.

The resulting chaos must be managed for the rest of a patient's life with diet, blood sugar measurement and insulin shots. Type 1 diabetes afflicts as many as 20 million people around the world, contributing to glaucoma, nerve damage, high blood pressure and stroke. In the U.S., it shortens life expectancy by more than a decade.

"The thing is, individuals who are at high risk can be identified," says Feyza Engin, a biomolecular chemistry professor at the University of Wisconsin-Madison and lead author of a new study published today in the journal Cell Metabolism. "They have autoantibodies in their blood serum, meaning we can actually tell who is going to develop Type 1 diabetes within a couple of years. But there's not much for clinicians to do but send them home, because there's no cure for Type 1 diabetes."

Engin's lab altered a line of mice genetically destined to develop Type 1 diabetes. Right before the immune attack usually begins, they removed from the beta cells alone a gene called IRE1-alpha, involved in the mouse cells' response to stress.

Engin expected removing this gene in insulin-producing cells would lead to accelerated diabetes. But the gene removal made a striking and unexpected difference in the mice.

"We expected the beta cells would die soon," Engin said. "Instead, my students told me that the blood glucose levels of the mice were becoming normal following an initial increase lasting a couple of weeks. I couldn't believe it. I said, 'What? No. Just measure it one more time.'"

The beta cells were indeed becoming normal insulin producers. But first they were taking a step backward into immaturity.

"Once we remove this gene, it's almost like the beta cells are undergoing a disguise," says Engin, who was joined by first author Hugo Lee, a graduate student, in publishing the results. "They lose their mature identity. They de-differentiate and exhibit features of progenitor cells, and express hormones of other cell types in addition to insulin."

If that de-differentiation happens before an auto-immune response puts the beta cells in danger, the T cells they meet respond differently.

"When they de-differentiate, they don't act like typical beta cells anymore. They reduce the expression of many genes that signal to immune cells, 'Come and eat me!'" Engin says. "Those signals go down, and that actually is altering the diabetogenic activity of T cells. They don't really recognize the beta cells as a problem anymore. They don't attack."

And then, just as importantly, the immature, de-differentiated beta cells re-differentiate into functional, mature beta cells.

"The mice experienced a little transient hyperglycemia. They have relatively high blood sugar, which isn't dangerous, for a few weeks," says Engin, whose lab is supported by the National Institutes of Health and the Juvenile Diabetes Research Foundation. "But then the beta cells get back to work, and make insulin like they're supposed to."

The T cells alter their activity and stick with the change, leaving the beta cells alone for as long as the lab has followed the mice so far.

"That's the beauty of it," Engin says. "Even after the beta cells come back, the T cells leave them alone. They still have no diabetogenic activity one year later, which is like 40 or 50 years in a human life."

Two drugs being tested in clinical trials for Type 1 diabetes target the stress response of beta cells -- including a drug whose efficacy Engin discovered in mice while working at Harvard University. Her lab's new findings could help guide the way candidate diabetes drugs in clinical trials are used, or help create new therapies. And they may have a similar effect in other auto-immune disorders -- like arthritis, lupus and multiple sclerosis -- in which a particular cell type's activity draws dysfunctional immune attention.

"We've found a very important time point where de-differentiation helps greatly reduce the immune cells' diabetogenic activity," Engin says. "If you can determine an appropriate cell targeted by auto-immune response, and make those victim cells less functional, less mature in the beginning, maybe they can avoid their role in the progress of other diseases, too."

What The Study Did: Head congestion is one of the most common symptoms experienced by astronauts during spaceflight. This observational study examined preflight and postflight head magnetic resonance images (MRIs) of 35 astronauts who participated in either a short-duration (30 days or less) Space Shuttle mission or a long-duration (greater than 30 days) International Space Station mission. Researchers  investigated whether there were differences in the development of certain physiological changes of the paranasal sinuses and mastoid air cells associated with symptoms of head congestion.

Authors: Donna R. Roberts, M.D., of the Medical University of South Carolina in Charleston, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamaoto.2020.0228)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the articles for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

How the novel coronavirus that causes COVID-19 made the leap from animals to humans is a puzzle that scientists are trying to solve as humanity comes to grip with the deadly pandemic sweeping the globe.

At the frontline of this scientific work is Professor Edward Holmes, an evolutionary virologist who holds a joint position with the School of Life and Environmental Sciences and the School of Medical Sciences at the University of Sydney.

He has been working closely with scientists in China and around the world to unlock the genetic code of SARS-CoV-2, which is the virus that causes COVID-19, to understand its origins and assist in the race other scientists are engaged in to find an effective vaccine.

Their work will also help in the monitoring and prevention of other viruses that could potentially transfer from wildlife into humans, causing what are known as zoonotic diseases.

Already this year, Professor Holmes has co-authored four papers on the novel coronavirus, including two of the earliest descriptions of the virus (published in Nature and The Lancet).

This week he publishes two more.

Brought forward for early publication on Thursday by Nature after peer review, the first paper identifies a similar coronavirus to the one now infecting humans in the Malayan pangolin population of southern China. Professor Holmes, a co-author, is the only non-China based academic on the paper.

Understanding the evolutionary pathway by which this novel coronavirus has transferred to humans will help us not only combat the current pandemic but assist in identifying future threats from other coronaviruses in other species.

This paper is an important part of solving that puzzle.

Professor Holmes said: "The role that pangolins play in the emergence of SARS-CoV-2 (the cause of COVID-19) is still unclear. However, it is striking is that the pangolin viruses contain some genomic regions that are very closely related to the human virus. The most important of these is the receptor binding domain that dictates how the virus is able to attach and infect human cells."

The paper identifies pangolins as possible intermediate hosts for the novel human virus that has emerged. The authors call for these animals and others to be removed from wet markets in order to prevent zoonotic transmission to humans.

Professor Holmes said: "It is clear that wildlife contains many coronaviruses that could potentially emerge in humans in the future. A crucial lesson from this pandemic to help prevent the next one is that humans must reduce their exposure to wildlife, for example by banning 'wet markets' and the trade in wildlife."

Just last week Nature Medicine published research co-authored by Professor Holmes with scientists from Scripps Research Institute in La Jolla California, the University of Edinburgh, Columbia University in New York and Tulane University, New Orleans.

That paper has dispelled the fanciful idea that the novel coronavirus was a manufactured biological agent.

Using comparative analysis of genomic data, the scientists show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus.

Professor Holmes said: "There is simply no evidence that SARS-CoV-2 - the cause of COVID-19 - came out of a lab. In reality, this is the sort of natural disease emergence event that researchers in the field like myself have been warning about for many years."

That paper has quickly become the highest ranked academic study of all time as measured by Altmetric, a company that monitors media coverage of research papers.

"The high Altmetric is a strong indication of the remarkable global interest in this topic," Professor Holmes said.

And today, Professor Holmes publishes a commentary in the journal Cell with his colleague Professor Yong-Zhen Zhang from the Shanghai Public Health Clinical Centre and the School of Life Science at Fudan University, Shanghai.

In that article they outline our current knowledge of what the genomic data reveals about the emergence of SARS-CoV-2 virus and discuss the gaps in our knowledge.

This includes taking samples from the Wuhan wet market where it is believed the virus originated. The paper says that "genome sequences of 'environmental samples' - likely surfaces - from the market have now been obtained and phylogenetic analysis reveals that they are very closely related to viruses sampled from the earliest Wuhan patients".

However, Professor Holmes and Professor Zhang are quick to point out that as "not all of the early [COVID-19] cases were market associated, it is possible that the emergence story is more complicated than first suspected".

The paper says that the SARS-CoV-2 virus is likely to become the fifth endemic coronavirus in the human population. It concludes that "coronaviruses clearly have the capacity to jump species boundaries and adapt to new hosts, making it straightforward to predict that more will emerge in the future".

How we respond to that will require more research to assist develop public health policy.

They point to policy and other measures to help prevent other coronaviruses becoming a health danger to humans. These include:

- Surveillance of animal coronaviruses in a variety of mammalian species. It is known that bats carry many coronaviruses, we know little about what other species carry these viruses and which has the potential to emerge in humans.

- Increase action against the illegal wildlife trade of exotic animals

- Removal of mammalian and perhaps avian wildlife from wet markets

BOSTON - It's now accepted that gut-barrier dysfunction and gut-derived chronic inflammation play a role in human aging, but how that process is regulated is still largely a mystery. A team led by Richard Hodin, MD, chief of the Division of General and Gastrointestinal Surgery at Massachusetts General Hospital (MGH) has uncovered an important piece of the puzzle which is described in the journal JCI Insight.

Studying mice and fruitflies, researchers found that the enzyme intestinal alkaline phosphotase (IAP) helped prevent intestinal permeability and gut-derived systemic inflammation, resulting in less frailty and extended life span. "Oral IAP supplementation in older mice significantly preserved gut barrier function and was associated with preserving the homeostasis of the gut microbiota during aging," said Hodin. "In other words, the enzyme maintained the composition of the gut bacteria and controlled the low-grade chronic inflammation that can happen with aging."

Because the scientists were using animal models, they were able to test blood from the portal venous system, which goes from the GI tract into the liver and then on through the rest of the body. "This gave us a more direct measure of what's passing across the gut barrier than blood from a human arm would," said Hodin, who began studying the function of IAP over a decade ago after connecting the dots in a couple of obscure papers suggesting the enzyme blocks an endotoxin called LPS. "I was studying IAP for other reasons, not knowing anything about its function," he said. "No one really did."

Because IAP is a naturally occurring enzyme that almost entirely remains in the gut rather than traveling throughout the system, Hodin believes it should prove nontoxic to humans, and those who are found have low levels, especially as they age, will simply be able to supplement. "Because IAP confers anti-inflammatory properties systemically," Hodin said, "it could have implications not only for inflammatory bowel diseases like Crohn's and ulcerative colitis, but also for other human conditions that we now know are linked to the gut and inflammation, such as obesity and diabetes." The team is already at work on the next steps toward getting FDA approval for a supplement.

What The Study Did: This study examined the medical records of 33 newborns born to women with COVID-19.

Author: Wenhao Zhou, M.D., of the National Children's Medical Center, Children's Hospital of Fudan University in Shanghai, China, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/ 

(doi:10.1001/jamapediatrics.2020.0878)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Ependymoma is a rare form of brain cancer that implicates children and is often tricky to diagnose. Since effective treatment options can be initiated only after a well-formed diagnosis, there is a dire need among the medical community to identify markers for ependymoma, which in turn, will help oncologists tailor therapy better. Richard Wong's and Mitsutoshi Nakada's team at Kanazawa University has now shown how one gene closely linked to ependymoma can help with not just diagnosis, but also treatment options for the condition.

A gene known as TPR shows an elevated presence in 38% of ependymoma cases. Thus, the team first sought out to investigate how an increase in the TPR gene correlated to the development of cancer cells. Each gene present in a cell contains a code for the creation of a specific protein. The TPR gene contains the code for an eponymous protein. Therefore, cancer samples from patients were assessed for the levels of TPR protein. As expected, levels of TPR were abnormally high in these tumor tissues.

The researchers then moved on to investigate whether these abnormal TPR levels could lead to cancer progression. For this purpose, mice were implanted with human ependymoma cancer tissue into their brains. The TPR gene was then deleted in these tissues so that the mice were unable to create the TPR protein. When the tumor tissues were subsequently analyzed, a reduction of cancer growth was seen. The TPR gene was thus vital for the growth of ependymoma tumors.

Deletion of the TPR protein is known to induce a process called autophagy within cells. Autophagy is initiated when a cell is under undue stress and results in the death of damaged cells. The patient tumor samples, with their high levels of TPR protein, showed little or no presence of autophagy. However, autophagy was remarkably high in the mice with TPR depletion. Ependymoma cells were thus spared of autophagic death due to the increased presence of TPR. These damaged cells continued to grow by circumventing the biological systems set up to keep them in check. The high TPR levels were also accompanied by an increase in HSF-1 and MTOR, molecules which are responsible for cell growth and survival.

Finally, the possibility of lowering TPR levels therapeutically to control the cancer was assessed. The mice were given a drug called rapamycin, which inhibits MTOR. The treatment not only led to decreased TPR levels, but also shrank the tumor tissues within their brains.

"Thus, TPR can serve as a potential biomarker, and MTOR inhibition could be an effective therapeutic approach for ependymoma patients", conclude the researchers. While looking out for increased levels of TPR in patients can help oncologists achieve a more comprehensive diagnosis, reducing TPR levels with the help of drugs can help keep the tumors in check.